Project Summary Nearly 600 fungal species are capable of causing human infections, affecting ~300 million people worldwide. Though most fungal infections are non-life threatening, mortality rates from several species can exceed 50%. Aspergillus fumigatus is the most prominent opportunistic fungal pathogen and is responsible for the deaths of ~100,000 people annually. Over the last several decades, a tremendous collection of work has been devoted to uncovering the mechanisms, molecules, and genes involved in A. fumigatus pathogenicity. Despite these efforts, treating and controlling A. fumigatus infections is more challenging than ever, largely due to the emergence of drug resistance and the increased usage of immunosuppressive treatments. New resources, tools, and approaches are needed to decipher the genes and polymorphisms underlying the complex nature of A. fumigatus pathogenicity. To date, A. fumigatus genomic research has lagged behind the pace at which DNA-sequencing technologies and computational biology methodologies have advanced. The ultimate goal of this proposal is to establish a community resource of A. fumigatus isolates and their associated genetic variant data in an effort to facilitate quantitative genetic and population genomic research. In Aim 1, we will create a publicly available collection of 230 genetically and phenotypically diverse A. fumigatus isolates that will be used as a reference panel for trait measurements. In Aim 2, we will sequence the genomes of each isolate and comprehensively catalogue genetic variation for use in A. fumigatus association mapping. In Aim 3, we will conduct a proof-of- concept genome-wide association analysis of virulence in the well-established wax moth larvae model system of invasive aspergillosis. At the conclusion of these studies we will have (i) created an invaluable tool that will allow for rapid, economical, and reliable association mapping of pathogenicity-associated traits, (ii) applied novel approaches to address and expand our knowledge of the genetic basis of A. fumigatus pathogenicity, and (iii) identified novel candidate genes to functionally examine in future studies. The results of this proposal have the potential to positively impact the hundreds of thousands of people burdened by A. fumigatus infection.